Process for the preparation of chiral nicotinic, quinolinic or benzoic acid imidazolinone herbicides

ABSTRACT

There is provided a stereospecific process for the preparation of essentially enantiomerically pure imidazolinone herbicides having the R-configuration via (R)2-amino-2,3-dimethylbutyronitrile.

This application claims priority from provisional application Ser. No.60/132,188, filed on May 3, 1999.

BACKGROUND OF THE INVENTION

Imidazolinone compounds, for instance, those described in U.S. Pat. Nos.4,188,487; 4,798,619 and 5,334,576, are highly potent, broad spectrum,environmentally benign, herbicidal agents. In general, the herbicidalactivity of the R-isomer is better than that of the racemicimidazolinone compound. A process to prepare chiral imidazolinones viathe resolved optically active 2-amino-2,3-dimethylbutyramide enantiomersis described in U.S. Pat. No. 4,683,324. Said aminoamide enantiomers areprepared via the hydrolysis of their chiral2-amino-2,4-dimethylbutyronitrile precursors and are difficult toisolate.

Therefore, it is an object of this invention to provide a stereospecificprocess to prepare chiral nicotinic, quinolinic or benzoic acidimidazolinone herbicidal agents directly from(R)2-amino-2,3-dimethylbutyronitrile without loss of optical purity andwithout the prior formation of (R)2-amino-2,3-dimethylbutyramide.

SUMMARY OF THE INVENTION

The present invention provides a stereospecific process to prepare achiral compound of formula I

wherein

X is N or CH; and

Y and Z are each independently H, C₁-C₄alkyl optionally substituted withone C₁-C₄alkoxy group or Y and Z may be takes together to form a group—CH═CH—CH═CH—

which process comprises the following steps:

a) reacting a compound of formula II

wherein X, Y and Z are as described hereinabove with at least one molarequivalent of (R)2-amino-2,3-dimethylbutyronitrile in the presence of anon-polar, essentially water-free solvent, optionally in the presence ofa tertiary amine, to form a first reaction mixture;

b) hydrolyzing said reaction mixture in aqueous acid to form an acidicsecond reaction mixture;

c) reacting said second reaction mixture with an excess of an aqueousbase at a temperature of about 20°-85° to form a basic third reactionmixture;

d) separating said third reaction mixture to obtain an aqueous phase;and

e) acidifying said aqueous phase to obtain the desired chiral formula Iimidazolinone compound.

DETAILED DESCRIPTION OF THE INVENTION

Chiral imidazolinone compounds having the R configuration demonstrateabout a 2-fold increase in herbicidal activity over the correspondingracemic mixture. Heretofore, (R)imidazolinone compounds were preparedfrom (R)2-amino-2,3-dimethylbutyramide due to the instability of the(R)2-amino-2,3-dimethylbutyronitrile compound. However, isolation ofsaid (R)aminoamide is difficult. Surprisingly, it has now been foundthat chiral imidazolinone herbicides may be prepared directly from(R)2-amino-2,3-dimethylbutyronitrile in the presence of a non-polaressentially water-free solvent with substantially complete retention ofenantiomeric purity from the (R)aminonitrile starting material to thefinal chiral imidazolinone herbicidal product. Advantageously, theprocess of the invention eliminates the need for the prior formation of(R)2-amino-2,3-dimethylbutyramide.

In accordance with the process of the invention, a formula II anhydrideis reacted with at least one molar equivalent of(R)2-amino-2,3-dimethylbutyronitrile in the presence of a non-polar,essentially water-free solvent, optionally in the presence of a tertiaryamine, to form a first reaction mixture; said reaction mixture ishydrolyzed with aqueous acid to form an acidic second reaction mixture;said second reaction mixture is treated with an excess of a base at atemperature of about 20°-90° C. to form a basic third reaction mixture;said third reaction mixture is separated to obtain an aqueous phase; andthe aqueous phase is acidified to obtain the desired chiral formula Iimidazolinone herbicide. The process is illustrated in flow diagram I.In the specification and claims, an asterisk designates the assymetriccarbon upon which the (R) configuration is conferred.

Solvents suitable for use in the process of the invention are non-polaressentially water-free solvents such as aromatic hydrocarbons (e.g.toluene, benzene, xylene, naphthalene and the like, preferably toluene),halogenated aromatic hdrocarbons (e.g. chlorobenzene, dichlorobenzenesand the like), hydrocarbons (e.g. pentanes, hexanes and the like),halogenated hydrocarbons (e.g. chloroform, methylene chloride,dichlorethane, and the like, esters (e.g. ethyl acetate, methylpropionate and the like), ethers (e.g. diethyl ether, tetrahydrofuran,dioxane and the like) or any of the conventional, preferably waterimmiscible, organic non-polar solvents.

Preferred non-polar solvents suitable for the process of the inventionare aromatic hydrocarbons, particularly toluene.

Tertiary amines suitable for use in the first step of the inventiveprocess are pyridine, 4-cyanopyridine, 4-picoline, 2-picoline, mixedpicolines, tri(C₁-C₄)alkylamine, quinoline or any of the conventionalorganic tertiary amines, preferably 4-picoline. The amine may be presentin amounts ranging from catalytic to excess amounts such as 10 mole % to4.0 molar excess.

Acids suitable for use in the process of the invention include strongmineral acids such as HCl or H₂SO₄, preferably H₂SO₄.

Bases suitable for use in the inventive process include alkali metalhydroxides or alkoxides, preferably hydroxides such as NaOH or KOH,preferably NaOH. These may be present at about 2 to 20molar-equivalents, preferably about 2 to 8 molar-equivalents.

It is also intended that the process of the invention embraces the useof (S)-2,3-dimethylbutyronitrile to prepare the corresponding(S)-imidazolinone herbicidal product.

In actual practice, a mixture of the formula II anhydride in anon-polar, essentially water-free solvent, preferably an aromatichydrocarbon, more preferably toluene, is treated with a 10% to 60%solution of (R)2-amino-2,3-dimethylbutyronitrile in a non-polar,essentially water-free solvent, preferably an aromatic hydrocarbon, morepreferably toluene, optionally in the presence of 10 mol % to 4.0 molarexcess, preferably about 10 mol % to 1.0 molar equivalent of 4-picoline,at a temperature of about 5° to 45° C., preferably about 5° C. to 30°C., to form a first reaction mixture; said mixture is treated with astrong mineral acid, preferably H₂SO₄, and water at temperatures ofabout 5° to 80° C., preferably about 20° C. to 60° C. to form an acidicsecond reaction mixture; said second mixture is treated with an excess,(about 2 to 20 moles per mole of acid used in the previous hydrolysisstep) of an aqueous alkali metal hydroxide or alkoxide, preferably analkali metal hydroxide, more preferably NaOH or KOH, of 10° or greaterconcentration on a weight basis at temperatures of about 15° C. to 90°C., preferably 20° C. to 85° C., to form a basic third reaction mixture;said third reaction mixture is separated to obtain an aqueous phase; andsaid aqueous phase is acidified with a strong mineral acid such as HCl,HBr or H₂SO₄, preferably H₂SO₄, to a pH of about 2 to 4 to obtain thedesired chiral formula I imidazolinone product. The product may beisolated using conventional procedures such as filtration, extractionwith a suitable solvent, chromatographic separation and the like,preferably filtration or extraction.

In order to facilitate a further understanding of the invention, thefollowing examples are presented primarily for the purpose ofillustrating certain more specific details thereof. The invention is notto be deemed limited thereby except as defined in the claims. Unlessotherwise noted, all parts are by weight. NMR designates nuclearmagnetic resonance. HPLC designates high performance liquidchromatography.

EXAMPLE 1 Preparation of(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl-5-methylnicotinicacid

A dry solution of (R)2-amino-2,3-butyronitrile (18.2 g, 0.163 mol) in120 ml of toluene is added to a mixture of5-methylpyridine-2,3-dicarboxylic acid anhydride (16.3 g, 0.10 mol) intoluene and 4-picoline (0.01 mol) over a 1 hour period at 10° C. Thereaction mixture is stirred 10° C. for 2 hr, treated with concentratedH₂SO₄ (6.33 ml, 11.65 g, 0.14 mol) and water under nitrogen at 30°-50°C., stirred for 5 hr at 50° C., treated with NaOH (51.4 g, 1.28 mol) asa 50% aqueous solution at 20° C. to 80° C. and treated with water. Thereaction mixture is cooled to room temperature and the phases areseparated. The aqueous phase is acidified to pH 3 with concentratedH₂SO₄, cooled and filtered. The filtercake is dried in vacuo at 60° C.for 72 hr to give the title product as a white solid, 16.2 g (58.7%yield) [α]_(D) ²⁵=+10.98°, 92.15%(R). Quantitative NMR analysisindicates 99.8% purity, 95% (R) isomer.

EXAMPLE 2 Preparation of(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl-5-nicotinic acid

A dry solution of (R)2-amino-2,3-dimethylbutyronitrile (168 g, 1.5 mol)in 750 ml of toluene is added to a mixture of pyridine-2,3-dicarboxylicacid anhydride (149.1 g, 1.0 mol) in toluene and 4-picoline (0.01 mol)over a 1 hr period at 10° C. The reaction mixture is stirred at 5°-10°C. for 1 hr., then stirred at 20° C. for 1 hr., treated with 200 ml H₂O,then treated quickly with 102 g of concentrated H₂SO₄ over a 3-5 minuteperiod at 20°-40° C., heated to 60° C., held at 60° C. for 2.5-3 hr.cooled to 20°, treated with 50% NaOH (412.5 ml, 631.2 g, 7.89 mol) at20° C. to 80° C., treated with 240 ml H₂O and cooled to roomtemperature. The phases are separated. The aqueous phase is acidified topH 3 with concentrated H₂SO₄, extracted with methylene chloride, dilutedwith 1 L H₂O and extracted twice more with methylene chloride. Theorganic extracts are combined, dried over MgSO₄ and concentrated invacuo to a thick slurry. The slurry is diluted with hexanes, stirred for45 minutes and filtered. The filtercake is dried in vacuo at 50°-55° C.to give the title product as a white solid, 219.4 g (84% yield), mp128-131° C. (bubbling). Quantitative NMR analysis indicates 95.4%purity, 95% R isomer.

EXAMPLE 3 Preparation of(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylicacid

A dry solution of (R)2-amino-2,3-dimethylbutyronitrile (11.8 g, 0.105mol, 91% R isomer) in toluene (37% w/w concentration) is added to astirred slurry of quinoline-2,3-dicarboxylic acid anhydride (19.9 g,0.10 mol) in a mixture of toluene and picoline (0.01 mol) at roomtemperature over a 45 minute period and stirred at room temperature for1 hour. The reaction mixture is then treated in essentially the samemanner as described in Example 1 to obtain the title product as a tansolid, 29.4 g (78% yield), 91.8% R isomer by chiral HPLC analysis.

EXAMPLE 4 Preparation of(R)5-Ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinicacid

A dry solution of (R)2-amino-2,3-dimethylbutyronitrile (12.3 g, 0.109mol, 93.1% R isomer) in toluene (32% w/w concentration) is added to astirred slurry of 5-ethylpyridine-2,3-dicarboxylic acid anhydride (17.7g, 0.10 mol) in a mixture of toluene and picoline (0.01 mol) at roomtemperature over a 40 minute period and stirred at room temperature for1 hour. The reaction mixture is then treated in essentially the samemanner as described in Example 1 to obtain the title product as anoff-white solid, 21.2 g (72% yield), 92.5% R isomer by chiral HPLCanalysis.

EXAMPLE 5 Preparation of(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(methoxymethyl)nicotinicacid

A dry solution of (R)2-amino-2,3-dimethylbutyronitrile (12.3 g, 0.109mol, 92.9% R isomer) in toluene (38w/w concentration) is added to astirred mixture of 5-(methoxymethyl)pyridine-2,3-dicarboxylic acidanhydride (19.3 g, 0.10 mol) in a mixture of toluene and picoline (0.01mol). The reaction mixture is then treated in essentially the samemanner as described in Example 1 to obtain the title product as a tansolid, 28.8 g (79% yield), 92.5% R isomer by chiral HPLC analysis.

What is claimed is:
 1. A process for the preparation of a chiralcompound of formula I

wherein X is N; and Y and Z are each independently H, C₁-C₄alkyloptionally substituted with one C₁-C₄alkoxy group or Y and may be takentogether to form a group —CH═CH—CH═CH— which process comprises thefollowing steps: a) reacting a compound of formula II

wherein X, Y and Z are as described hereinabove with at least one molarequivalent of chiral 2-amino-2,3-dimethylbutyronitrile

in the presence of a non-polar, essentially water-free solvent,optionally in the presence of a tertiary amine, to form a first reactionmixture; b) hydrolyzing said reaction mixture in aqueous acid to form anacidic second reaction mixture; c) reacting said second reaction mixturewith an excess of an aqueous base at a temperature of about 15° C. to90° C. to form a basic third reaction mixture; d) separating said thirdreaction mixture to obtain an aqueous phase; and e) acidifying saidaqueous phase to obtain the desired chiral formula I imidazolinonecompound.
 2. The process according claim 1 wherein the non-polaressentially water-free solvent is selected from the group consisting ofaromatic hydrocarbons, halogenated aromatic hydrocarbons, hydrocarbons,halogenated hydrocarbons, esters and ethers.
 3. The process according toclaim 2 wherein the solvent is an aromatic hydrocarbon.
 4. The processaccording to claim 3 wherein the non-polar, essentially water-freesolvent is toluene.
 5. The process according to claim 1 wherein the acidin steps b and e is HCl or H₂SO₄.
 6. The process according to claim 5wherein the acid is H₂SO₄.
 7. The process according to claim 1 whereinthe base in step c is an alkali metal hydroxide and the temperature isabout 15° C. to 90° C.
 8. The process according to claim 7 wherein thebase is NaOH.
 9. The process according to claim 1 having a formula IIcompound wherein X is N.
 10. The process according to claim 1 whereinthe chiral 2-amino-2,3-dimethylbutyronitrile is(R)2-amino-2,3-dimethylbutyronitrile.
 11. The process according to claim10 wherein the chiral formula I compound is selected from the groupconsisting of(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid;(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolincarboxylicacid;(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-methylnicotinicacid;(R)5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinicacid; and(R)2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(methoxymethyl)nicotinicacid.